SUMMARY Alzheimer?s disease is a burgeoning national epidemic and an effective treatment is urgently needed. It is now widely recognized that vascular disease contributes to Alzheimer?s disease and, in some cases, may be central to the process of neuronal degeneration. Cerebral amyloid angiopathy (CAA) is a vasculopathy produced when ?-amyloid forms a toxic encrustation on cerebral arterioles and capillaries; it independently contributes to cognitive impairment and predisposes elderly patients to intracerebral hemorrhage. CAA has emerged as a critical variable in the search for a treatment for AD, and is particularly important as mechanisms of cerebral ?- amyloid clearance are beginning to be better understood. Never-the-less, the most fundamental mechanisms of how ?-amyloid undermines the structural integrity of vessels remain unknown. We propose to study the microvascular network in AD and CAA by large-scale, three dimensional, microscopic imaging of optically cleared human tissue specimens. We hypothesize that this will show ?-amyloid deposits are closely linked to areas of vascular degeneration. Our main goals are 1) to produce a high-resolution three-dimensional model of the cerebral cortical microvascular network, including capturing changes associated with AD and CAA and 2) to determine whether ?-amyloid is present at sites of microhemorrhage and what morphological features are associated with vascular fragility. This work will answer fundamental questions about the link between vascular integrity and Alzheimer?s disease and provide a foundation for future work to better understand the molecular mechanisms of vascular fragility in CAA.